The primary objective of the Midwest Center for Structural Genomics (MCSG) will be to apply its structure determination pipeline to collaboratively determine the structures of targets nominated by the PSI:Biology Network and the broader biology community. The MCSG will devote a smaller fraction of its effort to contribute, together with its PSI colleagues, to a broader coverage of protein fold space by targeting proteins whose structures would provide the greatest insight into the relationships between sequence and structure. Finally, the MCSG will continue to drive three scientific programs: proteins associated with virulence in human pathogens, proteins overrepresented and associated with disease in human microbiomes and proteins involved in signaling and transcription regulation - areas we are already pursuing in collaboration with leaders in the scientific community. Our long-term goals are to provide high-quality structural models for a large number of biomedically and biologically important proteins and protein families, to overcome structure determination pipeline bottlenecks so that high-throughput (HTP) approaches are amenable to challenging proteins and protein complexes, and to develop advanced protein production methods for these protein families. As part of its mandate, the MCSG will also continue to develop and improve technology, and to refine rapid, highly integrated, and costeffective methods for de novo structure determination by X-ray crystallography using high-efficiency beamlines at third-generation synchrotron sources. Our ultimate goal is to build, together with our PSI colleagues, a foundation for 21st century structural biology where the structures of virtually any protein or protein complex is available to the biology community through the Protein Data Bank (PDB).